ABSTRACT The central goal of this proposal is to establish the accuracy of brain tumor perfusion imaging. Dynamic susceptibility contrast (DSC) MRI is one of the most widely used advanced imaging techniques in neuro- oncology. Multiple studies have shown how DSC-MRI measures of relative cerebral blood volume (rCBV) can differentiate glioma grades, tumor types and identify tumor components in non-enhancing glioma distinguish tumor recurrence from post-treatment effects, and predict tumoral response and patient survival after targeted therapy. Despite DSC-MRI's potential impact on clinical care, its broad scale integration has been slow, in large part from a lack of consensus about methodology and how to prevent potential rCBV inaccuracies. Although DSC relies on the assumption that gadolinium-based contrast agents (GBCA) remain within the vascular lumen, this condition is often violated in vivo. If not corrected for, contrast agent leakage effects lead to rCBV inaccuracy, misdiagnosis, and potentially mistreatment. While numerous leakage correction strategies exist, a fundamental limitation has prevented the standardization and wide-spread adoption of DSC-MRI methodology: To date, no study has validated the accuracy of leakage corrected rCBV measures in patients. The lack of validation impacts DSC-MRI standardization efforts, the establishment of rCBV thresholds for clinic use, multi-site comparisons and clinical trials. Given the importance of rCBV accuracy we propose to address this through two highly focused studies. First, we aim to validate rCBV accuracy by comparison to an intravascular reference standard in high-grade glioma patients. Multiple acquisition and analysis techniques will be investigated. Second, using a novel in silico digital phantom we aim to systematically define the range of DSC-MRI protocols that maintain consistent rCBV measurements. Impact on Healthcare: Our primary deliverable is to provide the neuro-oncology community with validated image acquisition and analysis methods for accurate rCBV mapping in brain tumor patients. Validated DSC-MRI techniques will improve its clinical reliability and justify its use across a range of clinical scenarios, including tumor localization, therapy response assessment, surgical and biopsy guidance, and multi-site clinical trials of conventional and targeted brain tumor therapies. !